Peripherally Selective CB1 Receptor Antagonists for Alcoholic Liver Disease

描述（由申请人提供）：以进行性肝病为特征的肝硬化是世界范围内慢性滥用乙醇导致发病的主要原因。此外，肝纤维化还与肝细胞癌的发病率增加有关，肝细胞癌通常是致命的。目前还没有批准的药物来治疗酒精性肝纤维化。内源性大麻素受体（CBRs），特别是CB 1 R，最近已经成为临床前验证的治疗肝纤维化和其他相关疾病的靶点。CB 1 R和CB 2 R都在中枢神经系统（CNS）中表达。它们也存在于包括肝脏在内的多种组织的外周。CB 1 R和CB 2 R在肝脏疾病的进展中发挥相互作用。虽然CB 1 R和CB 2 R在正常肝脏中少量表达，但在肝细胞和肝星状细胞（HSC）中，当肝损伤或酒精性肝病发作时，它们发生显著上调。过去的研究还表明，CB 1 R拮抗剂是进一步开发和测试治疗酒精性肝病的有希望的候选药物。目前可用的CB 1 R拮抗剂由于其对CNS的有害作用而不适合用于肝纤维化。例如，由Sanofi-Aventis开发的用于肥胖症的选择性CB 1 R拮抗剂SR 141716（Rimonabant（c））在患者中产生了不良的CNS相关副作用，包括抑郁和自杀意念。这是一个特别令人关注的人口众多的酗酒者谁患有抑郁症。这些副作用导致FDA拒绝在美国使用这种化合物，并在批准后从欧洲撤回。尽管存在这些局限性，但利莫那班治疗肥胖（RIO）试验和随访研究的数据表明，除了CNS相关效应外，SR 141716总体耐受性良好，并具有几种积极的非CNS相关特性，如改善血脂谱和胰岛素敏感性。这些结果还表明，在酒精性肝病和其他相关病因中靶向CB 1 R的有效策略是开发不能渗透血脑屏障（BBB）的外周限制性CB 1 R拮抗剂，这是本研究项目的总体目标。通过我们正在进行的NIAAA资助的小型研究基金（R 03 AA 017514），我们已经确定了基于核心SR 141716结构的CB 1 R拮抗剂，这些结构降低了通过BBB的渗透性。使用这些在CB 1 R具有酒精相关活性的早期化合物作为模板，通过合理的药物设计进行进一步的改进，我们希望开发和测试下一代化合物，作为药物开发的先导，通过以下具体目标治疗酒精性肝纤维化：通过目标1，我们建议合成SR 141716的其他类似物，其结构特性旨在限制其通过BBB的转运。通过目标2，我们建议使用功能性体外试验来表征这些合成的化合物。此外，我们还将研究啮齿动物中选定数量的活性化合物的药代动力学特性，包括BBB渗透性和半衰期。此外，我们建议进行基因表达谱实验，以比较和对比我们最好的导致SR 141716在稳定表达CB 1 R的肝星状细胞系中的全基因组效应。通过目标3，我们建议在酒精性脂肪变性的体内Lieber-DeCarli啮齿动物模型中进行我们最好的化合物的功效测试。我们将评估ALD的几种生物标志物，以监测测试化合物在这种良好建立的酒精性肝病模型中的功效。 公共卫生相关性：项目叙述酒精性肝病的死亡率很高，并增加患肝癌的机会。目前没有FDA批准的药物可用于治疗这种疾病。我们的目标是通过靶向一种称为1型大麻素受体的特定类型的蛋白质来开发治疗酒精性肝病的药物，这种蛋白质被认为是这种疾病的靶点。利用药物化学和药理学，我们建议合成和测试抑制1型大麻素受体功能的化合物。

DESCRIPTION (provided by applicant): Cirrhosis characterized by progressive liver disease is a leading cause of morbidity from chronic abuse of ethanol worldwide. In addition, hepatic fibrosis is also associated with increased rates of hepatocellular carcinoma, which is usually fatal. There is currently no approved drug to treat alcoholic liver fibrosis. The endocannabinoid receptors (CBRs), particularly CB1R, have recently emerged as pre-clinically validated targets to treat liver fibrosis and other related disorders. Both CB1R and CB2R are expressed in the central nervous system (CNS). They also exist peripherally in a variety of tissues including the liver. CB1R and CB2R play reciprocal roles in progression of liver disease. While CB1R and CB2R are marginally expressed in normal liver, they undergo marked upregulation upon liver injury or onset of alcoholic liver disease in hepatocytes and hepatic stellate cells (HSC). Past studies also indicate that antagonists of CB1R are promising candidates for further development and testing to treat alcoholic liver disease. Currently available CB1R antagonists are unsuitable for use in liver fibrosis due to their deleterious effects on the CNS. For example, the selective CB1R antagonist SR141716 (Rimonabant(c)), which was developed by Sanofi-Aventis for obesity, produced undesirable CNS-related side effects in patients including depression and suicidal ideation. This is a particular concern in a large population of alcoholics who suffer from depression. These side effects led the FDA to reject this compound for use in the US and it was withdrawn from Europe post-approval. In spite of these limitations, data from the Rimonabant for Obesity (RIO) trial and follow-up studies indicate that CNS related effects aside, SR141716 is well tolerated in general and has several positive non-CNS related properties, such as improved blood lipid profile, and insulin sensitivity in users. These results also indicate that an effective strategy to target CB1R in alcoholic liver disease and other related etiologies that would by-pass the CNS-related concerns of chronically antagonizing this receptor is to develop peripherally restricted CB1R antagonists that cannot permeate the blood-brain barrier (BBB), which is the overall goal of this research project. Through our ongoing NIAAA-funded small research grant (R03AA017514), we have identified CB1R antagonists based upon the core SR141716 structure that have reduced permeability across the BBB. Using these early compounds with pharmacologically relevant activity at CB1R as templates for further refinement through rational drug design, we expect to develop and test the next generation of compounds to serve as leads for medications development to treat alcoholic liver fibrosis through the following specific aims: Through aim 1 we propose to synthesize additional analogs of SR141716 with structural properties designed to limit their transport across the BBB. Through aim 2, we propose to characterize these synthesized compounds using functional in vitro assays. Further, we will also study pharmacokinetic properties of a select number of active compounds in rodents including BBB permeability and half-life. Additionally, we propose to conduct gene expression profiling experiments to compare and contrast the genome-wide effects of our best lead to SR141716 in a hepatic stellate cell-line stably expressing CB1R. Through aim 3, we propose to conduct efficacy testing of our best compound in an in vivo Lieber-DeCarli rodent model of alcoholic steatosis. We will evaluate several biomarkers of ALD to monitor efficacy of the test compound in this well-established model of alcoholic liver disease. PUBLIC HEALTH RELEVANCE: Project Narrative Alcoholic liver disease has a high mortality rate and increases the chance of developing liver cancer. There are no FDA-approved drugs available currently to treat this disease. Our goal is to develop drugs to treat alcoholic liver disease by targeting a particular type of protein called the type 1 cannabinoid receptor that has been implicated as a target for this disorder. Using medicinal chemistry and pharmacology, we propose to synthesize and test compounds that inhibit the function of type 1 cannabinoid receptors.